4-substituted-2-alkyl-3-phenyl-2h-1,2-benzothiazine-1,1-dioxides and processes for their production

ABSTRACT

4-substituted-2-alkyl-3-phenyl-2H-1,2-benzothiazine-1,1-dioxides having the following structural formula are disclosed   WHEREIN R1 is alkyl or aralkyl and R2 is hydrogen or acyl. These compounds are useful as anti-inflammatory agents.

United States Patent Zinnes et al.

[451 Sept. 19, 1972 [72] Inventors: Harold Zinnes, Rockaway; John Shave], Jr., Mendham, both of NJ.

[73] Assignee: Warner-Lambert Pharmaceutical Company, Morris Plains, NJ.

[22] Filed: Oct. 14, 1970 [21] Appl. No.: 80,788

[521 US. Cl ..260/243 R, 424/246, 260/240 F [51] Int. Cl. ..C07d 93/02 [58] Field of Search ..260/243 R [56] References Cited UNITED STATES PATENTS 3,591,584 7/1971 Lombardino ..260/243 3,459,748 8/ i969 Krapcho ..260/243 Primary Examiner-John M. Ford Attorney-Albert H. Graddis, Frank S. Chow, Neil D. Edwards, Edward G. Comrie and Anne M. Kelly [57] ABSTRACT 4-substituted-2-alkyl-3-phenyl-2l-ll ,Z-benzothiazine- 1,1-dioxides having the following structural formula are disclosed wherein R is alkyl or aralkyl and R, is hydrogen or acyl. These compounds are useful as anti-inflammatory agents.

7 Claims, No Drawings 4-SUBSTlTUTED-2-ALKYL-3-PHENYL-2H-l ,2- BENZOTHIAZINE-l l -DIOXIDES AND PROCESSES FOR THEIR PRODUCTION The present invention relates to 4-substituted-2- alkyl-3-phenyl-2H-l ,2-benzothiazine-l l -dioxides having the following structural formula:

wherein R is alkyl or aralkyl and R is hydrogen or acyl.

In the above definitions for R and R the term alkyl embraces both straight and branched alkyl radicals containing one to eight carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, n-amyl, and hexyl, 2-ethyl-2,3-dimethyl butyl and the like. The term aralkyl denotes groups such as benzyl. The term acyl" embraces the radical derived from a carboxylic acid, preferably that of an alkanoic acid having one to 18 carbon atoms, such as formic, acetic, butyric, propionic and the like, benzoic acid or palmitic acid.

The present invention also includes within its scope processes for the production of the above compounds as well as novel methods for treating inflammatory conditions.

The compounds of this invention are useful as antiinflammatory agents, particularly those local inflammatory conditions such as dermatitis, urticara and the like. For example, in a test conducted in accordance with the procedure set forth in Meier, et al, Experientia, Vol. 6, pp 469, 1950, the compounds of this invention when applied locally at a dose range of from about 25 to 100 milligrams/per kg of body weight to an inflamed site of a mammalian host, such as rats, guinea pigs and the like, are found effective in suppressing the growth of granuloma tissue which has been induced by the implantation of a cotton pellet.

In order to use the compounds of this invention, they are formulated into the usual dosage forms for topical application. For example, from about 0.l percent by weight to about percent by weight of the selected compound is blended with a dermatologically acceptable vehicle such as petrolatum, vanishing cream base, talc and the like and compounded into dosage forms such as ointments, creams and dusting powders. These dosage forms containing the selected compound or combinations thereof are applied liberally to an inflamed site two or three times daily.

According to the process of the invention, the above 4-substituted 1,2-benzothiazines are prepared in accordance with the reaction sequence set forth below.

Broadly speaking, starting compound ll is treated with a peroxide, typically hydrogen peroxide at about ice water temperature, in the presence of a base in an inert solvent to obtain compound in. Treatment of compound II] with an acid, typically boron trifluoride in an inert solvent such as methylene chloride gives a compound having formula IV. Refluxing compound IV with an aqueous acid results in decarbonylation yielding those compounds wherein R is hydrogen. Subsequent treatment of those compounds of this invention where R is hydrogen with a base such as sodium hydride results in the fonnation of a salt which is in turn acylated with an acyl halide or an acid anhydride to give those compounds of the invention wherein R is acyl.

The starting compound ll is known and is prepared in accordance with the procedure in J. Org. Chem. 30, 2241,0965).

intermediate compounds corresponding to Ill and W above are novel and they are also included within the scope of the present invention.

As it is obvious to those skilled in the art, by employing appropriately substituted starting materials, for example, where the aromatic rings are substituted by groups such as alkyl, aryl, alkoxy, amino, halogen, trifluoromethyl, nitro and the like, other 4-substitutedbenzothiazines can be readily obtained.

The following examples are given to further illustrate the invention.

EXAMPLE 1 3-Benzyl-3 ,a-epoxy-2-methyl-2l-l-l ,2-benzothiazin- 4( 3l-l)-one-l l -Dioxide To a solution of 18 g (0.06 mol) of 3-benzylidene-2- methyl-l ,2-benzothiazin-4( 3l-l)-one l ,l-dioxide in 300 ml of tetrahydrofuran was added ml of 30 percent aqueous hydrogen peroxide. To the stirred solution was slowly added 60 ml of 1.0 N sodium hydroxide, the temperature being maintained at 0 TO +5 during the addition. After stirring at this temperature for 30 minutes, the reaction mixture was poured into 3000 ml of ice-water and the resulting precipitate was collected and dissolved in dichloromethane. This solution was washed with water, dried over sodium sulfate, and evaporated to give a gummy residue. Trituration with petroleum ether (30-60) gave 15.5 g of white crystals, m.p. l20-123 dec which was of sufficient purity for use in the subsequent step. A portion was recrystallized from ethanol to give an analytical sample, m.p. l26-l28 dec. The material appeared to decompose on standing.

Anal. for CmHmNOqSZ EXAMPLE 2 EEQ 3-Formyl-2-methyl-3-phenyl-2H-l ,2-benzothiazin- 4(3H)-one-1,l-Dioxide A solution of 37.8 g (0.12 mol) of 3-benzyl3-,aepoxy-2-methyl-2H-1 ,2-benzothiazin-4(3H)-one-l ,1- dioxide in 1500 ml of dichloromethane was cooled to -5 and 300 ml of 46 percent boron trifluoride etherate was added. The resulting solution was allowed to stand at a temperature of 0 to 5 for 30 minutes and then poured into ice-water. The layers were separated and the organic layer was successively washed with water, in sodium hydroxide, and water. It was then dried over sodium sulfate and evaporated to a residue which was triturated with 50 ml of hot ether to give 23.5 g of crystals, m.p. 147148 (gas evol.). Recrystallization of a portion from a large volume of ether gave an analytical sample, m.p. 148-149 (gas evol.).

Anal. for C H NO S:

Calcd.: C 60.94H-4.16N -4.44S- 10.17

Found:C -6l.05 H -4.13 N-4.38 S- 10.32

EXAMPLE 3 NOHs \S/ 4-Hydroxy-2-methyl-3phenyl-2H-1,2-benzothiaiine 1,1-Dioxide A mixture of 15.7 g (0.05 mol) of 3-formyl-2-methyl- 3-phenyl-2H- l ,2-benzothiazin-4(3H)-one 1,1-dioxide, 200 ml of methanol, and 30 ml of 10 percent aqueous hydrochloric acid was refluxed for minutes. The solution was filtered while hit and concentrated to a volume of 75 ml. On standing at room temperature there was obtained 12.9 g of white crystals. The melting characteristics were dependent on the rate of heating. Samples immersed in the melting point bath at a rate of 1 per minute started to decompose at 132 and melted completely at 148. Samples kept at 132 for minutes melted completely. Recrystallization from methanol gave 1 1.0 g of product having the same melting characteristics.

Anal. for C, H, NO S:

Calcd.: C 67.70 H 4.56 N 4.87 S 11.16

Found: C- 62.84 H 4.58 N 4.91 S 11.22

EXAMPLE 4 /O\Ci(CHz)11CH3 NCH:

4 4-Palmitoxy-2-methyl-3-phenyl-2H-1 ,2-benzothiazine 1,1-Dioxide To a suspension of 0.03 mol of sodium hydride (55 percent mineral oil dispersion) in ml tetrahydrofuran, was added a solution of 8.61 g (0.03 mol) of 4-hydroxy-2-methyl-3-phenyl-2H-1 ,2- benzothiazine 1,1-dioxide in 50 ml of tetrahydrofuran, the temperature being maintained at 20. The mixture was stirred at this temperature for 2 hours and a solution of 8.25 g (0.03 mol) of palmitoyl chloride in 20 ml of tetrahydrofuran was added dropwise and stirring was continued at 20 for 2 hours. It was poured into 800 ml of cold 1 percent hydrochloric acid and extracted with dichloromethane. The organic layer was washed successively with cold 0.1 N sodium hydroxide and water, dried over sodium sulfate, and evaporated. The crystalline residue (17 g) was recrystallized from methanol-dichloromethane to give 9.5 g of product, m.p. 56.557.5.

Calcd.: C 70.82 H 8.24 N 2.66 S 6.10

Found: C 71.00 H 8.27 N 2.60 S 6.33

EXAMPLE 5 OCOCHa 4-Acetoxy-2-methyl-3phenyl-2H-1,2-benzothiazine 1,1-Dioxide To a suspension of 0.017 mol of sodium hydride (55 percent mineral oil dispersion) in 50 ml of tetrahydrofuran, was added a solution of 5.0 g (0.017 mol) of 4-hydroxy-2-methyl-3-phenyl-2H-l ,2- benzothiazine 1,1-dioxide in 50 ml of tetrahydrofuran, the temperature being maintained at 20. The mixture was stirred at this temperature for 2 hours and a solution of 1.36 g (0.017 mol) of acetyl chloride in 5 ml of tetrahydrofuran was added dropwise and stirring was continued at 20 for 2 hours. It was poured into 800 ml of cold 1 percent hydrochloric acid and extracted with dichloromethane. The organic layer was washed successively with cold 0.1 N sodium hydroxide and water, dried over sodium sulfate and evaporated. The residue was recrystallized from dichloromethane to give 4.5 g of product, m.p. 174-l 7 5.

Anal. for C H NO S:

Calcd.: C 61.99 H 4.59 N 4.25 S 9.73

Found: C 62.26 H 4.62 N 4.54 S 9.85

We claim:

1. A compound of the formula:

methanola. treating a compound of the formula: v

with a peroxide to give an epoxide of the formula:

b. treating said epoxide with an acid in an inert solvent to give a compound of the formula:

NR1 s ,9 f9.

and

c. refluxing said compound IV with an aqueous acid. 6. A compound of the formula:

wherein R, is alkyl of one to eight carbon atoms or benzyl.

' 7. A compound of the formula:

A CHO NR1 o o wherein nfis'lfifiBi he to eight carbon atoms or benzyl. 

2. A compound according to claim 1 which is 4-hydroxy-2-methyl-3-phenyl-2H,1,2-benzothiazine 1,1-Dioxide.
 3. A compound according to claim 1 which is 4-palmitoxy-2-methyl-3-phenyl-2H-1,2-benzothiazine 1,1-Dioxide.
 4. A compound according to claim 1 which is 4-acetoxy-2-methyl-3-phenyl-2H-1,2-benzothiazine 1,1-Dioxide.
 5. A process for producing a compound according to claim 1 wherein R2 is hydrogen which comprises a. treating a compound of the formula:
 6. A compound of the formula:
 7. A compound of the formula: 